Thrombus disease is caused by thrombosis and embolism. Under certain pathological conditions, blood clots may be formed from blood components in blood vessel. Blood clots come off from the sites where they form, and will partially or completely block veins or blood-supplying arteries in their flowing process along with the blood flow, causing a series of pathological processes, such as vascular or systematic ischemia, anoxia and necrosis. Common thrombus disease thrombosis, including myocardial infarction, cerebral thrombosis, deep vein thrombosis, pulmonary embolism, and peripheral arterial thromboembolism, seriously damage people's life and the quality of life. Coronary heart disease is an important kind of thrombus diseases, and includes myocardial infarction and angina pectoris. Each year about 0.8-1.5 million new patients suffer from coronary heart disease in China. Coronary heart disease ranks as the fourth leading cause of death, while cerebrovascular disease ranks second. In addition, although there is no specific statistics about the incidence of deep vein thrombosis, but according to a preliminary estimation, the number of deep vein thrombosis patients in China may reach one million. Moreover, with the improvement of people's living quality, the significant improvement of the national average life expectancy, and the increasing proportion of elderly population, the incidence of deep vein thrombosis will increase gradually, and become a common disease.
Thrombosis is caused by the activation of two systems, i.e., coagulation factors and platelets. Coagulation factors are a series of protein components participating in blood clotting. During the angiorhagia or under some pathological condition, these proteins are activated, and adhered together with platelets to form blood clots. There exist two coagulation systems in the body, i.e. endogenous and exogenous. The former refers to that the blood is contacted with abnormal surface to activate Coagulation factor XII. The latter refers to that due to tissue injury, Coagulation factor III is released, and therefore Coagulation factor VII is activated. Both can trigger a series of chain reactions, and converge at Coagulation factor X, which finally lead to the activation of prothrombin and the formation of fibrin.
In recent years, antithrombotic therapies with heparin, aspirin and warfarin have been widely used in clinic. Among them, warfarin inhibits the post-translational maturation of coagulation factors VII, IX, X and prothrombin, and has proven effective in both venous and arterial thrombosis. However, its usage is limited due to its narrow therapeutic index, slow onset of therapeutic effect, numerous dietary and drug interactions, and a need for monitoring and dose adjustment. Heparin is also the main drug in the antithrombotic therapy. But common heparin can't be orally absorbed, and the injection is not convenient. Therefore, more effective oral antithrombotic drugs will have great market demand in China.
Coagulation factor X is a good target for the antithrombotic treatment. First, coagulation factor X is upstream of thrombin in the coagulation cascade amplification. One coagulation factor X molecule can activate hundreds of thrombin molecules. Therefore, theoretically speaking, it would be more effective to inhibit coagulation factor X than to inhibit thrombin. Second, inhibition of coagulation factor X does not affect the thrombin that has been activated. Reversible inhibitors of coagulation factor X may not completely inhibit the generation of thrombin, while a small amount of thrombin can activate platelet to support the hemostatic process. Thus the inhibition of coagulation factor X might have relatively mild adverse effects of bleeding than thrombin. This was confirmed in animal models. Third, the indirect coagulation factor X inhibitor fondaparinux has been clinically successful, demonstrating that the inhibition of coagulation factors is indeed an effective means of anti-thrombosis.
In the conversion process of prothrombin into thrombin, Factor Xa is the most important drug target in the coagulation cascade. Factor Xa inhibitors can closely attach to the active site of Factor Xa, resulting in the inactivation of Factor Xa that is free or combined with fibrin so as to have the anti-coagulant effect. Compared with heparin with low molecular weight, factor Xa inhibitors can significantly reduce the occurrence of venous thrombosis, and does not increase the incidence of bleeding. Compared with warfarin, factor Xa inhibitors are convenient without the requirement for dosage adjustment and routine surveillance, and have little interaction with food and drugs so as to can be co-administrated with others.
At present, a series of patent applications with respect to factor Xa inhibitors have been disclosed, including WO2001047919, WO2008006479, WO2007137801, WO2006047528 and the like. In addition, there have been several coagulation factor X inhibitors in the abroad market, including the Rivaroxaban of Bayer, Apixaban of Bristol-Myers Squibb (BMS) and the like. Apixaban is jointly developed by BMS and Pfizer. It is another direct oral factor Xa inhibitor following Rivaroxaban, and is useful in preventing venous thrombosis in adult elective total hip or total knee arthroplasty, and was listed in the European Union in July 2011
Although the bleeding tendency of factor Xa inhibitors is lower than those of traditional anti-coagulants, the main clinical adverse reaction is still bleeding. Therefore it is a research focus in the field to reduce the risk of bleeding, and improve the therapeutic window.
Although a series of Factor Xa inhibitors with anti-thrombosis effect have been disclosed, it is still urgently demanded to develop new drugs with better efficacy and lower bleeding risk.